General Information About Central Nervous System (CNS) Embryonal Tumors
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization classification of nervous system tumors.[1,2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.
Embryonal tumors are a collection of biologically heterogeneous lesions that share the tendency to disseminate throughout the nervous system via cerebrospinal fluid (CSF) pathways. Although there is significant variability, histologically these tumors are grouped together because they are at least partially composed of hyperchromatic cells (blue cell tumors on standard staining) with little cytoplasm, which are densely packed and demonstrate a high degree of mitotic activity. Other histologic and immunohistochemical features, such as the degree of apparent cellular transformation along identifiable cell lineages (ependymal, glial, etc.), can be used to separate these tumors to some degree. However, a convention, which has been accepted by the World Health Organization (WHO), also separates these tumors based on presumed location of origin within the central nervous system (CNS). Molecular studies have substantiated the differences between tumors arising in different areas of the brain and give credence to this classification approach.
The pathologic diagnosis of embryonal tumors is primarily based on histological and immunohistological microscopic features. However, molecular genetic studies are employed increasingly to subclassify embryonal tumors. These molecular genetic findings are now being utilized for risk stratification and treatment planning.[5-8]
The most recent WHO categorization of embryonal tumors is as follows:
- CNS primitive neuroectodermal tumor (PNET).
- CNS neuroblastoma.
- CNS ganglioneuroblastoma.
- Atypical teratoid/rhabdoid tumor. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information about CNS atypical teratoid/rhabdoid tumors.)
Medulloblastomas are further subdivided, as noted in the Cellular and Molecular Classification of CNS Embryonal Tumors section of this summary.
Pineoblastoma, which in the past was conventionally grouped with embryonal tumors, is now categorized by the WHO as a pineal parenchymal tumor. Given that therapies for pineoblastomas are quite similar to those utilized for embryonal tumors, pineoblastomas are discussed in this summary. A somewhat closely aligned tumor, pineal parenchymal tumor of intermediate differentiation, has recently been identified, but is not considered an embryonal tumor and primarily arises in adults.[1,2]
- Extent of CNS disease at the time of diagnosis.
- Age at diagnosis.
- Amount of residual disease after definitive surgery.
- Tumor histopathology.
- Biological/molecular tumor cell characteristics.
It has become increasingly clear, especially for medulloblastomas, that outcome is also related to the molecular characteristics of the tumor, but this has not been definitively shown for other embryonal tumors.[4,7,10-12] Overall survival rates range from 40% to 90%, depending on the molecular subtype of the medulloblastoma and possibly other factors, such as extent of dissemination at time of diagnosis and degree of resection. Children who survive 5 years are considered cured of their tumor. Survival rates for other embryonal tumors are generally poorer, ranging from less than 5% to 50% and specifics are discussed within each subgroup in the summary.[13-16]
Embryonal tumors comprise 20% to 25% of primary CNS tumors (malignant brain tumors and pilocytic astrocytomas) arising in children. These tumors occur throughout the pediatric age spectrum but tend to cluster early in life. The incidence of embryonal tumors in children aged 1 to 9 years is fivefold to tenfold higher than is the incidence of embryonal tumors in adults.[17,18]
|Age Group (y)||Annual Incidence Rate (Cases per 1 Million)|
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.
The clinical features of childhood embryonal tumors depend on the location of the tumor and the age of the child at the time of presentation. Embryonal tumors tend to be quickly growing tumors and are usually diagnosed within 3 months of initial onset of symptoms.
In approximately 80% of children, medulloblastomas arise in the region of the fourth ventricle. Most of the early symptomatology is related to blockage of CSF and resultant hydrocephalus. Children with medulloblastoma are usually diagnosed within 2 to 3 months of onset of symptoms and commonly present with the following:
- Relatively abrupt onset of headaches.
- Unsteadiness, including truncal unsteadiness.
- Some degree of nystagmus.
Twenty percent of patients with medulloblastoma will not have hydrocephalus at the time of diagnosis and are more likely to present initially with cerebellar deficits. For example, more laterally positioned medulloblastomas of the cerebellum may not result in hydrocephalus, and because of their location, are more likely to result in lateralizing cerebellar dysfunction (appendicular ataxia) manifested by unilateral dysmetria, unsteadiness, and weakness of the sixth and seventh nerves on the same side as the tumor. Later, as the tumor grows towards the midline and blocks CSF, the more classical symptoms associated with hydrocephalus become evident.
Cranial nerve findings are less common, except for unilateral or bilateral sixth nerve palsies, which are usually related to hydrocephalus. At times, medulloblastomas will present explosively with the acute onset of lethargy and unconsciousness due to hemorrhage within the tumor.
In infants, the presentation of medulloblastoma is more variable and may include the following:
- Nonspecific lethargy.
- Psychomotor delays.
- Loss of developmental milestones.
- Feeding difficulties.
On examination, there may be bulging of the anterior fontanel due to increased intracranial pressure and abnormal eye movements, including eyes that are deviated downward (the so-called sun setting sign) due to loss of upgaze secondary to compression of the tectum of the midbrain.
Hereditary cancer predisposition syndromes associated with medulloblastoma
A small percentage of medulloblastoma cases arise in the setting of hereditary cancer predisposition syndromes. Syndromes known to be associated with medulloblastoma include the following:
- Turcot syndrome (related to germline mutations in APC).
- Rubinstein-Taybi syndrome (related to germline mutations in CREBBP).[22-24]
- Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, associated with germline PTCH1 and SUFU mutations).[25-28]
- Li-Fraumeni syndrome (related to germline mutations in TP53).[29,30]
- Fanconi anemia.[31,32]
Sometimes medulloblastoma may be the initial manifestation of the presence of germline mutations in these predisposition genes.
Other CNS embryonal tumors
For other embryonal tumors, presentation is also relatively rapid and depends on the location of the tumor in the nervous system. Pineoblastomas often result in hydrocephalus due to blockage of CSF at the third ventricular level and other symptoms related to pressure on the back of the brain stem in the tectal region. Symptoms may include a constellation of abnormalities in eye movements manifested by pupils that react poorly to light but better to accommodation, loss of upgaze, retraction or convergence nystagmus, and lid retraction (Parinaud syndrome). As they grow, these tumors may also cause hemiparesis and ataxia.
Supratentorial lesions, such as CNS neuroblastomas and ganglioneuroblastomas, will result in focal neurologic deficits, such as hemiparesis and visual field loss, depending on which portion of the cerebral cortex is involved. They may also result in seizures and obtundation. Medulloepitheliomas and ependymoblastomas may occur anywhere in the CNS and presentation is variable. Usually there is significant neurologic dysfunction associated with lethargy and vomiting.
Diagnostic and Staging Evaluation
Diagnosis is usually readily made by either magnetic resonance imaging (MRI) or computed tomography scan. MRI is preferable, as the anatomic relationship between the tumor and surrounding brain and tumor dissemination is better visualized.
After diagnosis, evaluation of embryonal tumors is quite similar, essentially independent of the histologic subtype and the location of the tumor. Given the tendency of these tumors to disseminate throughout the CNS early in the course of illness, imaging evaluation of the neuraxis by means of MRI of the entire brain and spine is indicated. Preferably this is done prior to surgery, in order to avoid postoperative artifacts, especially blood. Such imaging can be difficult to interpret and must be performed in at least two planes, with and without the use of contrast enhancement (gadolinium).
Following surgery, imaging of the primary tumor site is indicated to determine the extent of residual disease. In addition, lumbar CSF analysis is performed, if deemed safe. Neuroimaging and CSF evaluation are considered complementary, because as many as 10% of patients will have evidence of free-floating tumor cells in the CSF without clear evidence of leptomeningeal disease on MRI scan. CSF analysis is conventionally done 10 to 21 days following surgery. If CSF is obtained within 10 days of the operation, detection of tumor cells within the spinal fluid is possibly related to the surgical procedure. In most staging systems, if fluid is obtained in the first few days following surgery and found to be positive, the positivity must be confirmed by a subsequent spinal tap to be considered of diagnostic significance. In cases where obtainment of fluid by a lumbar spinal tap is deemed unsafe, ventricular fluid can be obtained; however, it may not to be as sensitive as lumbar fluid assessment.
Because embryonal tumors are rarely metastatic to the bone, bone marrow, or other body sites at the time of diagnosis, studies such as bone marrow aspirates, chest x-rays, or bone scans are not indicated, unless there are symptoms or signs suggesting organ involvement.
Additional diagnostic studies for patients with desmoplastic medulloblastoma
Patients with desmoplastic tumors with extensive nodularity should be carefully evaluated for stigmata of Gorlin syndrome. One report observed that medulloblastoma with extensive nodularity (MBEN) was associated with Gorlin syndrome in 5 of 12 cases. Gorlin syndrome, also called nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder in which those affected are predisposed to the development of basal cell carcinomas later in life, especially in skin in the radiation portal. The syndrome can be diagnosed early in life by detection of characteristic dermatological and skeletal features such as keratocysts of the jaw, bifid or fused ribs, macrocephaly, and calcifications of the falx.
Various clinical and biologic parameters have been shown to be associated with the likelihood of disease control of embryonal tumors after treatment. The significance of many of these factors have been shown to be predictive for medulloblastomas, although some are used to assign risk, to some degree, for other embryonal tumors. Parameters that are most frequently utilized to predict outcome include the following:[35,36]
In older studies, the presence of brain stem involvement for children with medulloblastoma was found to be a prognostic factor; it has not been found to be of predictive value in subsequent studies utilizing both radiation and chemotherapy.[33,35]
Extent of CNS disease at diagnosis
Patients with disseminated CNS disease at diagnosis are at highest risk for disease relapse.[34-36] Ten percent to 40% of patients with medulloblastoma have CNS dissemination at diagnosis, with infants having the highest incidence and adolescents and adults having the lowest incidence.
CNS primitive neuroectodermal tumors (PNETs) and pineoblastomas may also be disseminated at the time of diagnosis, although the incidence of dissemination may be somewhat less than that of medulloblastomas, with dissemination at diagnosis being documented in approximately 10% to 20% of patients.[13,14] Patients with CNS PNETs and pineoblastomas with disseminated disease at the time of diagnosis have a poor overall survival, with reported survival rates at 5 years ranging from 10% to 30%.[13-16]
Age at diagnosis
Age younger than 3 years at diagnosis (in the absence of histologic features of extensive nodularity) portends an unfavorable outcome for those with medulloblastoma and, possibly, other embryonal tumors.[37-40]
Amount of residual disease after definitive surgery
Determination of extent of resection has been supplanted by postoperative MRI measurement of the amount of residual disease after definitive surgery as a predictor of outcome.
In older studies, the extent of resection for medulloblastomas was found to be related to survival.[35,36,41,42] Some studies still utilize the extent of resection after surgery to separate patients into risk groups. In a Children's Oncology Group (COG) study involving over 400 children with nondisseminated medulloblastomas, patients with a subtotal resection did not have a different progression-free survival or overall survival than patients with total or near-total resections. In contrast, a contemporary German HIrnTumor and International Society of Paediatric Oncology (HIT-SIOP) study of 340 children reported that residual disease (>1.5 cm2) connoted a poorer 5-year event-free survival.
In patients with other forms of embryonal tumors, the extent of resection has not been definitively shown to impact survival.
For medulloblastomas, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analyses to correlate with outcome.[38,44,45] In prospective studies, immunohistochemical and histopathologic findings have not predicted outcome in children older than 3 years at diagnosis, with the exception of the anaplasia/large cell variant, which has been associated with poorer prognosis.[12,46] Several studies have observed that the histologic finding of desmoplasia, seen in patients aged 3 years and younger with desmoplastic medulloblastoma, especially MBEN, connotes a significantly better prognosis compared with outcome for infants and young children with classic or large cell/anaplastic medulloblastoma.[12,25,37-39]; [Level of evidence: 2A]
For other embryonal tumors, histologic variations have not been associated with differing outcome.
Biological/molecular tumor cell characteristics
A host of tumor cell characteristics have been associated with prognosis, primarily in children with medulloblastoma, including the following:
Genomic analyses (including RNA gene expression and DNA methylation profiles, as well as DNA sequencing to identify mutations) on both fresh-frozen and formalin-fixed, paraffin-embedded sections have identified molecular subtypes of medulloblastoma.[5-8,10,11,55,57-63] These subtypes include those characterized by WNT pathway activation and sonic hedgehog (SHH) pathway activation, as well as additional subgroups characterized by MYC or MYCN alterations and other genomic alterations.[5-8,10,11,55,57-62] Patients whose tumors show WNT pathway activation usually have an excellent prognosis, while patients with SHH pathway activated tumors generally show an intermediate prognosis. Outcome for the remaining patients is less favorable than that for patients with WNT pathway activation. Mutations in medulloblastoma cases are observed in a subtype-specific manner, with CTNNB1 mutations observed in the WNT subtype and with PTCH1, SMO, and SUFU mutations observed in the SHH subtype. The prognostic significance of recurring mutations is closely aligned with that of the molecular subtype with which they are associated.[6,64] At recurrence, the subtype remains unchanged from the original molecular subtype at diagnosis.
Refer to the Biologically/molecularly defined subtypes of medulloblastoma section of this summary for more information on the subtypes of medulloblastoma.
For CNS PNETs, integrative genomic analysis has also identified molecular subtypes with different outcomes. (Refer to the Cellular and Molecular Classification of CNS Embryonal Tumors section for more detailed information.)
Follow-up After Treatment
Relapse in children with embryonal tumors is most likely to occur within the first 18 months of diagnosis.[43,66] Surveillance imaging of the brain and spine is usually undertaken at routine intervals during and after treatment (refer to Table 2). The frequency of such imaging, designed to detect recurrent disease at an early, asymptomatic state, has been arbitrarily determined and has not been shown to clearly influence survival.[67-69] Growth hormone replacement therapy has not been shown to increase the likelihood of disease relapse.
|Surveillance Period||Frequency of Visits During Surveillance Period||Testing|
|First 3 years after diagnosis||Every 3 months||Physical exam|
|Imaging of the brain and spine every 3 months for the first two years; after year 2, imaging of the spine can be performed every 6 months|
|Endocrinology evaluation once a year|
|Neuropsychologic testing every 1–2 years|
|3–5 years after diagnosis||Every 6 months||Physical exam|
|Imaging of the brain and spine once a year|
|Endocrinology evaluation once a year|
|Neuropsychologic testing every 1–2 years|
|More than 5 years after diagnosis||Once a year||Physical exam|
|Imaging of the brain once a year|
|Endocrinology evaluation once a year|
|Neuropsychologic testing every 1–2 years (optional)|
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